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Gene Review

PCK1  -  phosphoenolpyruvate carboxykinase 1 (soluble)

Homo sapiens

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Disease relevance of PCK1

  • Linkage studies showed that PCK1 is not tightly linked to MODY in one large pedigree and exclude this diabetes candidate gene as the cause of MODY in this family [1].
  • Disregulated glyceroneogenesis: PCK1 as a candidate diabetes and obesity gene [2].
  • Because the gluconeogenic pathway contributes to the fasting hyperglycemia of type II diabetes, inhibitors of PEPCK may be useful in the treatment of diabetes [3].
  • Several protein-nucleic acid complexes are observed when nuclear extracts from hepatoma cells are assayed for binding to the cAMP response element found in the phosphoenolpyruvate carboxykinase-cytosolic (PEPCK-C) promoter [4].
  • This transcription factor binds to cAMP-response element 1 within the PEPCK promoter and may enhance its transcription during metabolic acidosis [5].

High impact information on PCK1


Chemical compound and disease context of PCK1


Biological context of PCK1

  • This assignment was confirmed using fluorescence in situ chromosomal hybridization which localized PCK1 to chromosome 20, band q13.31 [1].
  • In contrast, a second PPARgamma/RXR-binding element centered at -446 bp, PCK1, is not involved in adipocyte specificity because inactivation of this site did not affect transgene expression [13].
  • The aim of this study was to identify genetic polymorphisms in potential candidate genes for type 2 diabetes by sequencing all exons in the PCK genes (PCK1 and PCK2), and examining the association with type 2 diabetes and diabetic phenotypes in a Korean population (775 type 2 diabetic patients and 316 normal control subjects) [14].
  • RESULTS: Although no significant associations between the genetic polymorphisms in PCK genes and the risk of type 2 diabetes were detected, in further haplotype analysis, one of the common haplotypes, PCK1 ht3, revealed susceptibility to type 2 diabetes (p=0.006) [14].
  • The common assumption is that mutations in PCK1 lead to excessive glucose production through hepatic gluconeogenesis [2].

Anatomical context of PCK1


Associations of PCK1 with chemical compounds


Physical interactions of PCK1

  • Thus, AUF1 binds to multiple destabilizing elements within the 3'-UTR that participate in the rapid turnover of the PEPCK mRNA [22].
  • We found that the RA receptor can bind to sequences within the PEPCK-TRE and contribute to RA responsiveness of the PEPCK gene [23].

Regulatory relationships of PCK1

  • Furthermore, PGC-1alpha phosphorylation by p38 was necessary for FFA-induced activation of the PEPCK promoter [24].
  • The overexpression of the dominant-negative CREB prevented FFA-induced activation of the PEPCK promoter [24].
  • These results show that ATF-2 can stimulate transcription of the PEPCK-C promoter and support a role for stress inducible kinases in the maintenance of PEPCK-C expression [4].

Other interactions of PCK1


Analytical, diagnostic and therapeutic context of PCK1


  1. cDNA sequence and localization of polymorphic human cytosolic phosphoenolpyruvate carboxykinase gene (PCK1) to chromosome 20, band q13.31: PCK1 is not tightly linked to maturity-onset diabetes of the young. Stoffel, M., Xiang, K.S., Espinosa, R., Cox, N.J., Le Beau, M.M., Bell, G.I. Hum. Mol. Genet. (1993) [Pubmed]
  2. Disregulated glyceroneogenesis: PCK1 as a candidate diabetes and obesity gene. Beale, E.G., Hammer, R.E., Antoine, B., Forest, C. Trends Endocrinol. Metab. (2004) [Pubmed]
  3. Crystal structure of human cytosolic phosphoenolpyruvate carboxykinase reveals a new GTP-binding site. Dunten, P., Belunis, C., Crowther, R., Hollfelder, K., Kammlott, U., Levin, W., Michel, H., Ramsey, G.B., Swain, A., Weber, D., Wertheimer, S.J. J. Mol. Biol. (2002) [Pubmed]
  4. Activating transcription factor-2 regulates phosphoenolpyruvate carboxykinase transcription through a stress-inducible mitogen-activated protein kinase pathway. Cheong, J., Coligan, J.E., Shuman, J.D. J. Biol. Chem. (1998) [Pubmed]
  5. Mechanism of increased renal gene expression during metabolic acidosis. Curthoys, N.P., Gstraunthaler, G. Am. J. Physiol. Renal Physiol. (2001) [Pubmed]
  6. The DEAD-box RNA helicase Vad1 regulates multiple virulence-associated genes in Cryptococcus neoformans. Panepinto, J., Liu, L., Ramos, J., Zhu, X., Valyi-Nagy, T., Eksi, S., Fu, J., Jaffe, H.A., Wickes, B., Williamson, P.R. J. Clin. Invest. (2005) [Pubmed]
  7. A susceptibility locus for early-onset non-insulin dependent (type 2) diabetes mellitus maps to chromosome 20q, proximal to the phosphoenolpyruvate carboxykinase gene. Zouali, H., Hani, E.H., Philippi, A., Vionnet, N., Beckmann, J.S., Demenais, F., Froguel, P. Hum. Mol. Genet. (1997) [Pubmed]
  8. Promoter polymorphism in PCK1 (phosphoenolpyruvate carboxykinase gene) associated with type 2 diabetes mellitus. Cao, H., van der Veer, E., Ban, M.R., Hanley, A.J., Zinman, B., Harris, S.B., Young, T.K., Pickering, J.G., Hegele, R.A. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  9. Structural and functional analysis of the human phosphoenolpyruvate carboxykinase gene promoter. O'Brien, R.M., Printz, R.L., Halmi, N., Tiesinga, J.J., Granner, D.K. Biochim. Biophys. Acta (1995) [Pubmed]
  10. Insulin represses phosphoenolpyruvate carboxykinase gene transcription by causing the rapid disruption of an active transcription complex: a potential epigenetic effect. Hall, R.K., Wang, X.L., George, L., Koch, S.R., Granner, D.K. Mol. Endocrinol. (2007) [Pubmed]
  11. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cool, B., Zinker, B., Chiou, W., Kifle, L., Cao, N., Perham, M., Dickinson, R., Adler, A., Gagne, G., Iyengar, R., Zhao, G., Marsh, K., Kym, P., Jung, P., Camp, H.S., Frevert, E. Cell metabolism. (2006) [Pubmed]
  12. Regulation of renal amino acid transporters during metabolic acidosis. Moret, C., Dave, M.H., Schulz, N., Jiang, J.X., Verrey, F., Wagner, C.A. Am. J. Physiol. Renal Physiol. (2007) [Pubmed]
  13. Adipose expression of the phosphoenolpyruvate carboxykinase promoter requires peroxisome proliferator-activated receptor gamma and 9-cis-retinoic acid receptor binding to an adipocyte-specific enhancer in vivo. Devine, J.H., Eubank, D.W., Clouthier, D.E., Tontonoz, P., Spiegelman, B.M., Hammer, R.E., Beale, E.G. J. Biol. Chem. (1999) [Pubmed]
  14. Association of a polymorphism in the gene encoding phosphoenolpyruvate carboxykinase 1 with high-density lipoprotein and triglyceride levels. Shin, H.D., Park, B.L., Kim, L.H., Cheong, H.S., Kim, J.H., Cho, Y.M., Lee, H.K., Park, K.S. Diabetologia (2005) [Pubmed]
  15. Cloning and reporter analysis of human mitochondrial phosphoenolpyruvate carboxykinase gene promoter. Suzuki, M., Yamasaki, T., Shinohata, R., Hata, M., Nakajima, H., Kono, N. Gene (2004) [Pubmed]
  16. Underexpressed Coactivators PGC1{alpha} AND SRC1 Impair Hepatocyte Nuclear Factor 4{alpha} Function and Promote Dedifferentiation in Human Hepatoma Cells. Mart??nez-Jim??nez, C.P., G??mez-Lech??n, M.J., Castell, J.V., Jover, R. J. Biol. Chem. (2006) [Pubmed]
  17. Species having c4 single-cell-type photosynthesis in the chenopodiaceae family evolved a photosynthetic phosphoenolpyruvate carboxylase like that of kranz-type c4 species. Lara, M.V., Chuong, S.D., Akhani, H., Andreo, C.S., Edwards, G.E. Plant Physiol. (2006) [Pubmed]
  18. Expression of phosphoenolpyruvate carboxykinase gene in human adipose tissue: induction by rosiglitazone and genetic analyses of the adipocyte-specific region of the promoter in type 2 diabetes. Duplus, E., Benelli, C., Reis, A.F., Fouque, F., Velho, G., Forest, C. Biochimie (2003) [Pubmed]
  19. Human PCK1 encoding phosphoenolpyruvate carboxykinase is located on chromosome 20q13.2. Yu, H., Thun, R., Chandrasekharappa, S., Trent, J.M., Zhang, J., Meisler, M.H. Genomics (1993) [Pubmed]
  20. Conserved amino acids within CCAAT enhancer-binding proteins (C/EBP(alpha) and beta) regulate phosphoenolpyruvate carboxykinase (PEPCK) gene expression. Jurado, L.A., Song, S., Roesler, W.J., Park, E.A. J. Biol. Chem. (2002) [Pubmed]
  21. Functional inhibitory cross-talk between constitutive androstane receptor and hepatic nuclear factor-4 in hepatic lipid/glucose metabolism is mediated by competition for binding to the DR1 motif and to the common coactivators, GRIP-1 and PGC-1alpha. Miao, J., Fang, S., Bae, Y., Kemper, J.K. J. Biol. Chem. (2006) [Pubmed]
  22. 3'-Untranslated region of phosphoenolpyruvate carboxykinase mRNA contains multiple instability elements that bind AUF1. Hajarnis, S., Schroeder, J.M., Curthoys, N.P. J. Biol. Chem. (2005) [Pubmed]
  23. CCAAT-enhancer-binding protein alpha (C/EBP alpha) is required for the thyroid hormone but not the retinoic acid induction of phosphoenolpyruvate carboxykinase (PEPCK) gene transcription. Park, E.A., Song, S., Olive, M., Roesler, W.J. Biochem. J. (1997) [Pubmed]
  24. p38 Mitogen-activated protein kinase mediates free fatty acid-induced gluconeogenesis in hepatocytes. Collins, Q.F., Xiong, Y., Lupo, E.G., Liu, H.Y., Cao, W. J. Biol. Chem. (2006) [Pubmed]
  25. The genes coding for phosphoenolpyruvate carboxykinase-1 (PCK1) and neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) map to human chromosome 20, extending the known region of homology with mouse chromosome 2. Pilz, A.J., Willer, E., Povey, S., Abbott, C.M. Ann. Hum. Genet. (1992) [Pubmed]
  26. Identification of a thyroid hormone response element in the phosphoenolpyruvate carboxykinase (GTP) gene. Evidence for synergistic interaction between thyroid hormone and cAMP cis-regulatory elements. Giralt, M., Park, E.A., Gurney, A.L., Liu, J.S., Hakimi, P., Hanson, R.W. J. Biol. Chem. (1991) [Pubmed]
  27. Broad expression of fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase provide evidence for gluconeogenesis in human tissues other than liver and kidney. Yánez, A.J., Nualart, F., Droppelmann, C., Bertinat, R., Brito, M., Concha, I.I., Slebe, J.C. J. Cell. Physiol. (2003) [Pubmed]
  28. Physical and genetic interactions of cytosolic malate dehydrogenase with other gluconeogenic enzymes. Gibson, N., McAlister-Henn, L. J. Biol. Chem. (2003) [Pubmed]
  29. Light Regulation of the Photosynthetic Phosphoenolpyruvate Carboxylase (PEPC) in Hydrilla verticillata. Rao, S., Reiskind, J., Bowes, G. Plant Cell Physiol. (2006) [Pubmed]
  30. Site-directed mutagenesis of Lys600 in phosphoenolpyruvate carboxylase of Flaveria trinervia: its roles in catalytic and regulatory functions. Gao, Y., Woo, K.C. FEBS Lett. (1995) [Pubmed]
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